Search

Pathogenicity assessment of DNA variants in disease genes to explain their clinical consequences is an integral component of diagnostic molecular testing. The International Society for Gastrointestinal Hereditary Tumors (InSiGHT) has developed specific criteria for the interpretation of mismatch repair (MMR) gene variants. Here, we performed a systematic investigation of 24 MLH1 and MSH2 variants. The assessments were done by analyzing population frequency, segregation, tumor molecular characteristics, RNA effects, protein expression levels, and in vitro MMR activity. Classifications were confirmed for 15 variants and changed for three, and for the first time determined for six novel variants. Overall, based on our results, we propose the introduction of some refinements to the InSiGHT classification rules. The proposed changes have the advantage of homogenizing the InSIGHT interpretation criteria with those set out by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium for the BRCA1/BRCA2 genes. We also observed that the addition of only few clinical data was sufficient to obtain a more stable classification for variants considered as "likely pathogenic" or "likely nonpathogenic." This shows the importance of obtaining as many as possible points of evidence for variant interpretation, especially from the clinical setting.

Aims and background. Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. Methods. A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLITH-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. Results. Five-year survival rates were 0.73 (95% Cl, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% Cl, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P= 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% Cl, 0.51-0.981 for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). Conclusions. Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal, AIMS AND BACKGROUND: Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. METHODS: A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. RESULTS: Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). CONCLUSIONS: Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related co

Genetic counseling is a medical process aimed at providing information about disease risks for hereditary conditions, For adult-onset diseases, such as cancer, the main purpose consists in formulating probability estimates of disease appearance, along with details on preventive or follow-up measures, The process of genetic counseling has been substantially modified by the availability of molecular tests to identify mutant gene carriers, So far, 16 autosomal dominant genes associated with cancer susceptibility have been cloned, Four of these, which encode for components of the DNA mismatch repair machinery, have been implicated in hereditary non-polyposis colorectal cancer, one of the most common hereditary cancer syndromes, Genetic counseling and testing in hereditary non-polyposis colorectal cancer is associated with several problems that are common to other hereditary conditions (psychologic consequences, confidentiality, genetic ''discrimination'', testing of miners, prenatal diagnosis) and peculiar Po the specific condition (incomplete penetrance, genotypic and phenotypic heterogeneity, limits of currently available tests), Pbi such reasons, genetic testing should be performed in qualified research laboratories and restricted to highly selected families. In this way, pilot studies? involving both clinicians and researchers, can be undertaken with the aim of providing comprehensive results, potentially applicable to other cancer-predisposing conditions.

Three main lines of approach were followed during the tenure of this Grant: (1) An 'indirect in vitro study' in which normal recipient received drugs and whose normal red cells were tested before and after drug administration for a possible stimulatory (i.e. hemolytic) effect. Sulphalene has such an effect, whereas chloroquine and WR 142490 AE have no stimulatory action on normal red cells. (2) A 'direct in vitro study' in which drugs obtained as pure chemical from W.R.A.I.R. were tested directly 'in vitro' with normal red cells. All drugs tested had a significant stimulatory effect on the hexose monophosphate shunt (HMS) of normal red cells. (3) Animal studies in which drugs were administered to normal rabbits either through esophageal tubing or via intramuscular injections. This last route was the best one. Nitrofurantoin at the dosage of 30 and 50 mg i.m. caused in some animals a significant stimualation of the HMS of their red cells.